CN1764447A - Use of tanshinone derivates as cholinesterase inhibitors in treating related diseases - Google Patents
Use of tanshinone derivates as cholinesterase inhibitors in treating related diseases Download PDFInfo
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- CN1764447A CN1764447A CNA200480007753XA CN200480007753A CN1764447A CN 1764447 A CN1764447 A CN 1764447A CN A200480007753X A CNA200480007753X A CN A200480007753XA CN 200480007753 A CN200480007753 A CN 200480007753A CN 1764447 A CN1764447 A CN 1764447A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/537—Salvia (sage)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
This present invention provides a new use of tanshinone derivatives as acetylcholinesterase inhibitors and in treating diseases associated with the depletion of acetylcholine such as cognitive impairment including Alzheimer's disease, insomnia, vascular dementia, memory loss, disorders of attention, and other sleeping disorders. The active compounds are commonly found in the root of Salvia genus, particularly Salvia miltiorrhiza, Danshen.
Description
The cross reference document of related application
It is 10/396,862 interests that the application requires the U.S. Patent Application Serial Number of the same title submitted on March 24th, 2003, and the present invention is for referencial use with its whole specific reference.
Invention field
The invention provides the new purposes of tanshinone derivative as acetylcholinesteraseinhibitors inhibitors, and such as the new purposes in the acetylcholine of the cognitive impairment consume treating correlative diseases.
Background of invention
Alzheimer (AD) is a kind of neurodegenerative diseases, has 11% and 50% the crowd who surpasses 65 years old and 85 years old ill respectively.The healing case that does not also have at present AD.One of neuro pathology's performance among the AD is exactly the consume of the main neurotransmitter of basal forebrain-acetylcholine.At present unique medicine of AD being treated by the FDA approval just is based on its inhibition activity to acetylcholinesterase (AChE), thereby recovers levels of acetylcholine in synapse.
Acetylcholine (ACh) is a kind of in the various neurotransmitters in the brain, and is a kind of important neurotransmitter in the neuromuscular junction.It can also regulate some parasympathetic nervous system, and causes smooth muscle contraction, vasodilation, secretion to increase and reduce heart rate.ACh not only reacts to the niacin receptor, also muscarinic receptor is reacted.
In parkinsonian patient, always there is the equilibrium problem between dopamine and the levels of acetylcholine.The consume of dopamine always causes the relative rising of levels of acetylcholine.In these patients, the excessive stimulation of cholinoceptor can cause this patient's hand tremor to be trembled or health requires impaired in the neuromuscular junction.
ACh has important effect in memory and awareness in obtaining.The consume of ACh can cause memory and carry out the forfeiture of ADL.Alzheimer is exactly to be the disease of characteristics with cholinergic deficient in the brain.
The treatment of AChE inhibitor, donepezil (Donepezil) can improve significantly the rapid eye movement behavior disorder (Rapid eye movement behavior disorder, RBD) and related symptoms.
The effect of acetylcholinesterase (AChE) is degraded ACh.
The inhibitory action that is caused by acetylcholinesterase can have several forms, or directly combines with active center paddy (gorge), or combines with the allosteric regulatory site.
The avtive spot of AChE is buried in center valley, and this path is being prolonged on the surface of the described enzyme of distance 20 dusts.
Butyrylcholine esterase (BuChE) is present in the blood plasma widely.It can be in neuromuscular junction the hydrolysis acetylcholine, finish the task identical with AChE.The non-specific BuChE that suppresses with AChE suppresses always can cause neurotoxicity.
The AChE inhibitor is a class important drugs of treatment Alzheimer.
The FDA approved four kinds of medicines that carry out AD treatment as the AChE inhibitor.These medicines comprise donepezil (Aricept
TM), ENA-713 (Exelon
TM), galantamine (Galantamine, Reminyl
TM) and tacrine (Tacrine, Cognex
TM).
To the investigation of Chinese medicine prescription with hundreds of years clinical experiences show Radix Salviae Miltiorrhizae often be used to releive spirit and such as promote blood flow, stimulate pass through, in the treatment prescription of other pharmacological properties such as menoxenia, dysmenorrhea and alleviating pain.
In the prior art of Chinese medicine, Radix Salviae Miltiorrhizae, red sage root are the formula components of " Tianwang Buxin Dan ".This prescription is mainly used in Cure for insomnia, excited and memory problem.The Radix Salviae Miltiorrhizae that minute quantity is only arranged in this prescription.Radix Salviae Miltiorrhizae seldom uses as single medicinal material.As mentioned above, the major function of Radix Salviae Miltiorrhizae is " nourish heart and allay excitement " (Tang W, Eisenbrand G, Chinese Drugs of Plant Origin, Springer-Verlag Berlin Heidelberg 1992.) in this prescription.
In modern Chinese medicine, Radix Salviae Miltiorrhizae is considered to a kind of effective blood-activating formula.Radix Salviae Miltiorrhizae can increase coronary blood flow and reduce crown resistance, and produces vasorelaxation action.It also has anti-platelet aggregation and calm effectiveness (Tang W, Eisenbrand G, Chinese Drugs of Plant Origin, Springer-Verlag Berlin Heidelberg 1992, middle hospital pharmacy, the Guangdong college of traditional Chinese medicine compiles. the Guangdong People's Press .).
In the also recommended hepatic injury and hepatic fibrosis (Tang W, Eisenbrand G, Chinese Drugs of Plant Origin, Springer-VerlagBerlin Heidelberg 1992.) that is used to prevent to cause of Radix Salviae Miltiorrhizae by viral hepatitis.
Owing to have the character of invigorating blood circulation, Radix Salviae Miltiorrhizae also be used to menoxenia, amenorrhea and TREATMENT OF DYSMENORRHOEA (pharmacology of Chinese materia medica, Wang Junmo chief editor. Shanghai science tech publishing house).
Injection of danshen can strengthen flow velocity (Yang et al, Studies on Chinese Patent 1979 Medicine (1): 8) in aorta and left side circumflex coronary artery.
Treated with Radix Salviae Miltiorrhizae can be improved or resist by the acute myocardial ischemia of inductive rabbit of pituitary hormone or rat (Chemistry of Nature Drugs Section, Faculty of Pharmacy, 1980.).
Radix Salviae Miltiorrhizae can strengthen crown flow velocity and to heart ischemia with dabbling again protection effectiveness (ZhouW et al., Protective effect of danshen during myocardial ischemia andreperfusion:an isolated rat heart study.Am J Chin Med 1990 arranged; 18 (1-2): 19-24.).
Recently prove, Radix Salviae Miltiorrhizae can weaken balloon injury in cholesterol is fed the rabbit body abdomen endarterium thickens (Chen.Y.L.et al., Salvia miltiorrhiza inhibits intimal hyperplasiaand monocyte chemotactic protein-1 expression after balloon injury incholesterol-fed rabbits., J Cell Biochem.83:484-493,2001.).
Recent research also shows, magnesium tanshinoate B (Magnesium tanshinoate B, MTB), a kind of reactive compound that derives from Radix Salviae Miltiorrhizae, oxidative modification (Karmin O.et al., Magnesium tanshinoate B (MTB) inhibits low densitylipoprotein oxidation.Life Sci 2001 Jan 12 that can suppress low density lipoprotein, LDL (LDL); 68 (8): 903-12.).
The hot water extract of Radix Salviae Miltiorrhizae has fibrosis effectiveness to inductive rat liver fibrosis, the aspartate transaminase concentration of this rat, alanine aminotransferase concentration, alkaline phosphatase concentration, total bilirubin and total cholesterol level significantly raise (Nan J.X.et al., Anti-fibrotic effects of ahot-water extract from Salvia Miltiorrhiza root on liver fibrosis induced bybiliary obstruction in rats.J Pharm Pharmacol.2001 Feb; 53 (2): 197-204.).
Find that cryptotanshinone (cryptotanshinone) and dihydrotanshinone I (dihydrotanshinone I) have antibacterial activity (Lee D.S.et al. to the wide spectrum gram-positive bacterium, Antibacterialactivities of cryptotanshinone and dihydrotanshinone I from a medicinal herb, Salvia miltiorrhiza Bunge.Biosci Biotechnol Biochem 1999 Dec; 63 (12): 2236-9.).
Aspect immunology, compare with cryptotanshinone and Tanshinone I (Tanshinone I), dihydrotanshinone demonstrates activity (Kang B.Y.et al., the Inhibition of interleukin-12 and interferon-gammaproduction in immune cells by tanshinones from Salvia miltiorrhiza.Immunopharmacology.2000 Sep of effective inhibition interleukin 12 (IL-12) and gamma interferon (IFN-gamma) generation; 49 (3): 355-61.).
Recently confirmed the anticholinesterase activity of Salvia Lavandulaefolia.Different with our claim, this inhibitory action is by monoterpenoid (Camphora and 1, the 8-eucalyptole) (the Perry NS that causes, Houghton PJ, Theobald A, Jenner P, Perry EK, In-vitro inhibition of humanerythrocyte acetylcholinesterase by salvia lavandulaefolia essential oil andconstituent terpenes.J Pharm Pharmacol.2000 Jul; 52 (7): 895-902.).
In the small-scale clinical trial, the garden-sage extract is to effective (the Akhondzadeh S of slight treatment to the moderate Alzheimer, Noroozian M, Mohammadi M, Ohadinia S, Jamshidi AH, Khani M, Salvia officinalis extract in the treatment of patientswith mild to moderate Alzheimer ' s disease:a double blind, randomized andplacebo-controlled trial.J Clin Pharm Ther.2003 Feb, 28 (1): 53-59.).
Summary of the invention
So, the object of the present invention is to provide the treatment acetylcholine esterase disease relevant, especially acetylcholine shortage or the pharmaceutical composition of disease, said composition comprises the pharmaceutical composition and the medicine acceptable carrier of the active component for the treatment of effective dose, this active component is selected from the chemical compound or the acceptable salt of its medicine of cryptotanshinone, dihydrotanshinone I, Tanshinone I, and the two mixture of the mixture of the mixture of described chemical compound or its drug acceptable salt or this.
Another object of the present invention is to provide the treatment acetylcholine to lack the relevant disease or the method for disease, comprise the delivery of active ingredients that the patient is carried out dose therapeutically effective, this active component is selected from cryptotanshinone, dihydrotanshinone I, Tanshinone I chemical compound or the acceptable salt of its medicine, and the two mixture of the mixture of the mixture of described chemical compound or its drug acceptable salt or this.
Another purpose of the present invention is to provide acceptable salt in cryptotanshinone, dihydrotanshinone I, Tanshinone I chemical compound or its pharmacy, and the two mixture of the mixture of the mixture of described chemical compound or its drug acceptable salt or this lacks purposes in relevant disease or the disease medicine at preparation treatment acetylcholine.
Brief description of drawings
Figure 1 shows that the hAChE inhibitory action of red sage root water extract and ethanol extraction.
The Radix Salviae Miltiorrhizae active component of selecting in Figure 2 shows that is to the inhibitory action of hAChE.
Figure 3 shows that the active component selected in the Salvia japonica Thunb. inhibitory action to hAChE.
Fig. 4 a is depicted as the inhibition of cryptotanshinone to hAChE and hBChE.
Fig. 4 b is depicted as the inhibition of dihydrotanshinone to hAChE and hBChE.
Fig. 5 a is depicted as the MTT cytotoxicity of active component of the present invention to neuronal cell line SHSY5Y.
Fig. 5 b is depicted as the MTT cytotoxicity of active component of the present invention to mice neuronal cell line N1E-115.
Detailed Description Of The Invention
The pharmaceutical composition for the treatment of cholinesterase relevant disease of the present invention or illness comprises active component and the medicine acceptable carrier for the treatment of effective dose, described active component is selected from compound or the acceptable salt of its medicine of Cryptotanshinone, dihydrotanshinone I, Tanshinone I, and the two mixture of the mixture of the mixture of described compound or its drug acceptable salt or this.
The tanshinone derivative that is present in the red sage root comprises Cryptotanshinone, dihydrotanshinone, Tanshinone I and the Tanshinone I I with following chemical constitution. Yet in the present invention, described active component does not comprise Tanshinone I I.
The cryptotanshinone dihydrotanshinone I
Tanshinone I Tanshinone I I
The reactive compound of TANSHINONES has faintly acid.So, in the present invention, term " acceptable salt in the pharmacy " is defined as those alkaline metal salts such as sodium salt or potassium salt, such as the alkali salt of calcium salt or magnesium salt, such as containing trimethylamine, triithylamine, pyridine, picoline, dicyclohexylamine or N, the organic ammonium salt of the salt of N '-Dibenzylethylenediamine.
Among the present invention employed term " active compound " or " active component " or " effective ingredient " be defined as above-described active TANSHINONES compound or its salt or this two mixture or the extract of salvia.
Be selected from Radix Salviae Miltiorrhizae (Salvia miltiorrhiza), Salvialavandulaefolia, Salvia divinorum and garden-sage (Salvia officinalis) plant optimization among the present invention.More preferably, the plant of using among the present invention is a Radix Salviae Miltiorrhizae.The extract of described plant preferably comes from the root of this plant.
The extract of described plant comprises water extract and C
1-4The alkanol extract.Hot water extract and C
1-4The alkanol extract is preferred.Ethanol extraction most preferably.
The term " treatment effective dose " that the present invention uses or " effective dose " mean the effective dose for the active component that will realize its intended purposes.This dosage can be according to patient's symptom, sex, age and body weight, medication, administration time and at interval and characteristic, adjustment and kind of pharmaceutical preparation, special active component or the like and change.It is appreciated for those skilled in the art that and aspect dosage, do not have specific restriction.Generally the dosage of active component is about every day each patient 0.005mg to 500mg, is preferably 0.1mg to 300mg, and more preferably 1mg is divided into one to four part of administration usually to 100mg.Yet in most of the cases, effectively every day, dosage range was extremely about 25mg/kg body weight of about 0.05mg/kg, was preferably about 0.1mg/kg to about 10mg/kg body weight, carried out administration with single or separate doses.Yet, in some cases, be necessary to use the dosage outside the above restriction, by prescription doctor decision.
The pharmaceutical composition that is used for administration of the present invention can comprise that at least a reactive compound and the combination in any that can accept form with medicine has drug acceptable carrier.
The term " drug acceptable carrier " that the present invention uses refers to that this active component of promotion that uses is processed into the excipient or the adjuvant of preparation in pharmacy.Said preparation can be by oral, intramuscular, intraperitoneal, subcutaneous or intravenous administration.Preferably, described preparation, particularly those include percentage by weight and are about 0.01-99.99% such as tablet, dragee, suppository and capsular preparation and suitable solution, are preferably active component and excipient and/or the adjuvant of 25-75%.
The excipient that is fit to that the present invention uses comprises the filler such as polysaccharide, for example lactose or sucrose, mannitol or sorbitol, cellulose derivative, magnesium sulfate, such as the calcium phosphate of tricalcium phosphate or calcium hydrogen phosphate, and such as the bonding agent of gelatinized corn starch, for example corn starch, wheaten starch, rice fecula, potato starch, gelatin, tragacanth and/or polyvinylpyrrolidone.
The adjuvant that is fit to that the present invention uses comprises fluid regulation agent and lubricant, for example Talcum, Silicon stone, stearic acid or its salt (such as magnesium stearate) and/or Polyethylene Glycol.Provide suitable bag quilt to the sugar-coat core, if necessary, it can tolerate gastric juice.For this purpose, spissated polysaccharide solution can be adopted, arabic gum, Talcum, polyvinylpyrrolidone (polyvinyl pyrrolidione), Polyethylene Glycol and/or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture arbitrarily can be contained.In order to produce the bag quilt of tolerance gastric juice, i.e. enteric coating adopts and such as the suitable cellulose preparation of acetylcellulose phthalic acid ester or hydroxypropylmethyl cellulose phthalate.Can in tablet or sugar-coat bag quilt, add dyestuff or pigment.
Compositions among the present invention can be formulated into the injection system such as intravenous, subcutaneous and intramuscular injection, the form of suppository or my humble abode tablet.Generally accepted method is come the pharmaceutical preparation of preparation example such as injection, suppository, sublingual tablet, tablet and capsular dosage form in employing this area.
, if desired, pH regulator agent, buffer agent, solubilizing agent, suspending agent, stabilizing agent and antiseptic can be mixed in the described active ingredient during injection in preparation, carry out the preparation of intravenous, subcutaneous or intramuscular injection agent subsequently according to conventional methods.
The example of solubilizing agent comprises polyoxyethylene hydrogenated castor oil (polyoxyethylenehydrogenated castor oil), polysorbate80, nicotiamide, polyethylene glycol oxide Arlacel-20, Polyethylene Glycol and Castor Oil Fatty Acid ethyl ester.The example of suspending agent comprises methylcellulose, polysorbate80, hydroxyethyl-cellulose, arabic gum, powdered tragacanth, sodium carboxymethyl cellulose and polyethylene glycol oxide Arlacel-20.
The example of stabilizing agent comprises sodium sulfite, sodium pyrosulfite and ester, examples of preservatives bag p-oxybenzene acid methyl ester, p-oxybenzene acetoacetic ester, sorbic acid, phenol, cresol and chlorocresol.
In the present invention, when reactive compound or composition oral administration, can adopt the form of tablet or capsule or aqueous solution or suspension.When adopting tablet, normally used carrier comprises lactose, mannitol and corn starch, and adds the lubricant such as magnesium stearate usually.If the employing capsule form, reactive compound in hard gelatin capsule with exsiccant form administration, or at the gel or the liquid carrier that are fit to, liquid macrogol or intersect in the glue form administration in Perle for example.When the oral waterborne suspension of needs, active component can be mixed with emulsifying agent and suspending agent.If necessary, can also add some sweeting agent and/or flavoring agent.
The disease or the disease that adopt active substance of the present invention to treat are meant disease or the disease that those are relevant with acetylesterase.In the present invention, described disease or patient comprise those cognitive impairments such as presenile dementia, insomnia, Alzheimer.Examples of disorders of the present invention comprises attention deficit disorder, vascular dementia and rapid eye movement behavior disorder (RBD).
The preparation of salvia miltiorrhiza water extract
Buy Radix Salviae Miltiorrhizae 10 grams that come from Hebei (Hibei) from Hong Kong Tongrentang company limited.Boiled 45 minutes under red sage root refluxed in the 80ml distilled water.Filter well-done extract, subsequently limpid filtrate is carried out lyophilization.With the lyophilization thing of powder type weigh (2g).
Embodiment 2
The preparation of salvia miltiorrhiza ethanol extraction
With the exsiccant Radix Salviae Miltiorrhizae of 10g soaked overnight in the 50ml dehydrated alcohol.Preserve this unfiltered extract and whole process repeated (promptly adopting other 50ml dehydrated alcohol to soak this medical herbs once more).Total 100ml extract is carried out lyophilization after with the 3M filter paper filtering.To be emplastic lyophilised material weigh (100mg).
Embodiment 3
| Cryptotanshinone | 0.01g |
| Corn starch | 95.99g |
| Magnesium stearate | 4g |
With all components mix homogeneously and make 100.
Embodiment 4
| The extract that obtains among the embodiment 2 | 0.4g |
| The 50%DMSO aqueous solution | 100ml |
The ethanol extraction of gained among the embodiment 2 is dissolved in 100ml 50%DMSO aqueous solution to obtain working solution.
Embodiment 5
| Dihydrotanshinone I | 0.1g |
| Corn starch | 0.5g |
| Lactose | 1.87g |
| Magnesium stearate | 0.03g |
With dihydrotanshinone I, corn starch and lactose uniform mixing.In mixture, add little water.With gained filtration of material and dry.In mixture, add magnesium stearate and uniform mixing.Adopt pelleter that this product is made sheet.Every heavy 250mg also contains the 10mg active component.
Biological activity test
Ellman analyzes
Adopt the Ellman analytical method that the cholinesterase inhibitor that is fit to is screened.Human acetylcholinesteraseisomer in the buffer (hAChE) is joined in test chemicals// TCM extract, and then add Acetylthiocholine (ATCI) substrate and EllmanShi reagent (5 ' 5-, two sulfur-two-(2-nitrobenzoate), DTNB).By the thiocholine that discharges the AChE inhibitory activity is monitored, this thiocholine forms the glassy yellow product with the DTNB reaction subsequently.Use spectrophotometer to detect the optical density of gained colour developing product.
The ethanol extraction that will obtain from the water extract and the embodiment 2 of embodiment 1 acquisition is dissolved in 20mg/ml 50%DMSO, and dilution subsequently becomes 10,20,50,80,100 μ g/ml and analyzes to carry out Ellman.
The Ellman that carries out on 96 orifice plates as described below analyzes: (the 100mM sodium phosphate buffer, default quantitative water pH7.4) or ethanol extraction (as mentioned above) mix with 0.1 hAChE of unit (buying in Sigma) in analysis buffer.Through (promptly 10 minutes) behind the of short duration preincubate, (5 ' 5-, two sulfur-two-(2-nitrobenzoate), DTNB) mixing mutually joins mixture in the aperture again with the 12.5mM Acetylthiocholine (ATCI) and the 10mM of same amount.After 10 minutes, at 415nm 96 orifice plates are carried out optical density and detect.Optical density is inverse ratio with the inhibition activity.
Testing result as shown in Figure 1, the hAChE that the water extract of the red sage root of 50 μ g/ml demonstrates moderate suppresses, active inhibition is higher than 80% and the ethanol extraction of 50 μ g/ml is to hAChE.
Equally also the anticholinesterase activity to selected Radix Salviae Miltiorrhizae active component detects.They are former catechu (phenol) aldehyde (protocatechealdehyde, molecular weight 138.12), tanshinone (molecular weight 294), Tanshinone I (molecular weight 276), cryptotanshinone (molecular weight 296), carnosic acid B (salvianic acid B, molecular weight 718) and dihydrotanshinone I (molecular weight 278).All these comes from Nat'l Pharmaceutical ﹠ Biological Products Control Institute of Chinese Bureau of Drugs Supervision.
The active component of selecting is dissolved in 50%DMSO.In this analysis, do not recommend to use 100%DMSO, because that can reduce enzymatic activity.
The former catechu of active component (phenol) aldehyde (molecular weight 138.12), cryptotanshinone (molecular weight 296), carnosic acid B (molecular weight 718) and the dihydrotanshinone I of selecting (molecular weight 278) carried out Ellman to be analyzed.Carry out 10 times of dilutions that maximum concentration reaches 40 μ M (as Fig. 2).
To active component cryptotanshinone (molecular weight 296), Tanshinone I (molecular weight 276), tanshinone (molecular weight 294), dihydrotanshinone I (molecular weight 278) and the galanthamine (galanthamine that selects, galantamine, molecular weight 368.3) (in contrast) carry out Ellman and analyze.Carry out maximum concentration reach 80 μ M 10 times of dilutions (as Fig. 3).
Galanthamine is the medicine that the FDA approval is used for the treatment of Alzheimer.
In all tested chemical drugss, have only cryptotanshinone and dihydrotanshinone I to show intensive AChE inhibitory action, its IC50 is respectively about 5-8 μ M and about 0.5-0.8 μ M (Fig. 2 and Fig. 3).On the other hand, Tanshinone I shows the AChE inhibitory action of moderate, and its IC50 is about 70 μ M.The former catechu of the diterpenoids of structurally associated (phenol) aldehyde, tanshinone and carnosic acid B be not almost to the inhibitory action of AChE.
In order to detect cryptotanshinone and dihydrotanshinone I specificity, in analyzing, Ellman adopt butyrylcholine esterase (hBchE) to substitute AChE for AChE.HBchE can enrichment in erythrocyte, is named as false esterase, has high homology with AChE.Can provide serious cholinergic side effect with the non-specific binding of hBchE.
Except adopting hBchE (available from Sigma), carry out Ellman as mentioned above and analyze.Also adopt simultaneously the parallel Ellman of carrying out of AChE to analyze to compare.Compare with BchE, cryptotanshinone and dihydrotanshinone I all demonstrate the selectivity higher to AChE (Fig. 4 a and Fig. 4 b).
MTT analyzes
Utilize the MTT analysis that the toxicity of the main hAChE inhibitor of selection is detected.Consider that the cell that only has metabolic activity just can remove tetrazolium salts MTT and form the formazen dyestuff.The OD at 540nm place detected value directly and viable count proportional.
In neuronal cell line SHSY5Y and mice neuronal cell line N1E-511, do not detect cryptotanshinone and the dihydrotanshinone I of 1 μ M and the significant cytotoxicity (Fig. 5 a and Fig. 5 b) that Tanshinone I produces of 1-50 μ M.
It is reported, the cytotoxicity that is caused by tanshinone in cell reduces under a cloud by removing alicyclic diradical realization (Zhao B.L., Jiang W., Zhao Y., Hou J.W., Xin W.J., Scavenging effects of salvia miltiorrhiza on free radicals and its protectionfor myocardial mitochondrial membranes from ischemia-reperfusion injury.Biochem Mol Biol Int.1996 May, 38 (6): 1171-82.).
Although below invention has been described, from above-mentioned detailed description of the present invention, variation and modification that the present invention is made are conspicuous to those skilled in the art.Should be appreciated that all these variations, modification and equivalent thereof all should comprise within the scope of the appended claims.
Claims (17)
1. the treatment acetylcholine lacks the pharmaceutical composition of relevant disease or disease, described pharmaceutical composition comprises the active component and the medicine acceptable carrier for the treatment of effective dose, described active component is selected from the chemical compound or the acceptable salt of its medicine of cryptotanshinone, dihydrotanshinone I, Tanshinone I, and the two mixture of the mixture of the mixture of described chemical compound or its drug acceptable salt or this.
2. pharmaceutical composition as claimed in claim 1, it comprises that percentage by weight is the active component of 0.01-99.99%.
3. pharmaceutical composition as claimed in claim 1, wherein said active component are cryptotanshinone, dihydrotanshinone I or Tanshinone I.
4. pharmaceutical composition as claimed in claim 1, wherein said active component is from the extract of Salvia.
5. pharmaceutical composition as claimed in claim 4, wherein said Salvia are selected from Radix Salviae Miltiorrhizae, Salvia lavandulaefolia, Salvia divinorum and garden-sage.
6. pharmaceutical composition as claimed in claim 5, wherein said extract is from red sage root.
7. as the described pharmaceutical composition of arbitrary claim in the claim 4 to 6, wherein said extract is water extract or ethanol extraction.
8. pharmaceutical composition as claimed in claim 1, wherein said disease or disease comprise presenile dementia, insomnia, Alzheimer, attention disorders, vascular dementia and rapid eye movement behavior disorder (RBD).
9. the treatment acetylcholine lacks the relevant disease or the method for disease, comprise the delivery of active ingredients that the patient is carried out dose therapeutically effective, described active component is selected from cryptotanshinone, dihydrotanshinone I, Tanshinone I chemical compound or the acceptable salt of its medicine, and the two mixture of the mixture of the mixture of described chemical compound or its drug acceptable salt or this.
10. method as claimed in claim 9, wherein said active component is with the dosed administration of 1mg to 100mg every day.
11. method as claimed in claim 9, wherein said active component are cryptotanshinone, dihydrotanshinone I or Tanshinone I.
12. method as claimed in claim 9, wherein said active component is from the extract of Salvia.
13. method as claimed in claim 12, wherein said Salvia are selected from Radix Salviae Miltiorrhizae, Salvia lavandulaefolia, Salvia divinorum and garden-sage.
14. method as claimed in claim 12, wherein said extract is from red sage root.
15. as the described method of arbitrary claim in the claim 12 to 14, wherein said extract is water extract or ethanol extraction.
16. method as claimed in claim 12, wherein said disease or disease comprise presenile dementia, insomnia, Alzheimer, attention disorders, vascular dementia and rapid eye movement behavior disorder (RBD).
17. cryptotanshinone, dihydrotanshinone I, Tanshinone I chemical compound, or acceptable salt in its pharmacy, and the two mixture of the mixture of the mixture of described chemical compound or its drug acceptable salt or this lacks relevant disease or the purposes in the disease medicine at preparation treatment acetylcholine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/396,862 US20040191334A1 (en) | 2003-03-24 | 2003-03-24 | Use of transhinone derivates as cholinesterase inhibitors in treating related diseases |
| US10/396,862 | 2003-03-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1764447A true CN1764447A (en) | 2006-04-26 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200480007753XA Pending CN1764447A (en) | 2003-03-24 | 2004-03-19 | Use of tanshinone derivates as cholinesterase inhibitors in treating related diseases |
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| Country | Link |
|---|---|
| US (1) | US20040191334A1 (en) |
| CN (1) | CN1764447A (en) |
| WO (1) | WO2004084884A1 (en) |
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-
2003
- 2003-03-24 US US10/396,862 patent/US20040191334A1/en not_active Abandoned
-
2004
- 2004-03-19 WO PCT/CN2004/000227 patent/WO2004084884A1/en active Application Filing
- 2004-03-19 CN CNA200480007753XA patent/CN1764447A/en active Pending
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| CN110012901B (en) * | 2019-04-12 | 2021-06-01 | 西北农林科技大学 | Diluting preparation for preserving boar semen at normal temperature |
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2004084884A1 (en) | 2004-10-07 |
| US20040191334A1 (en) | 2004-09-30 |
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